Dilated cardiomyopathy myosin mutants have reduced force-generating capacity

Geeves, Michael A. and Leinwand, Leslie A. and Spudich, James A. and Ruppel, Kathleen M. and Kawana, Masataka and Choe Yu, Elizabeth and Svicevic, M. and Mijailovich, Srboljub M. and Vera, Carlos and Ujfalusi, Zoltán (2018) Dilated cardiomyopathy myosin mutants have reduced force-generating capacity. Journal of Biological Chemistry, . ISSN 0021-9258. (doi:https://doi.org/10.1074/jbc.RA118.001938) (Full text available)

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Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) can cause arrhythmias, heart failure, and cardiac death. Here, we functionally characterized the motor domains of five DCM-causing mutations in human β-cardiac myosin. Kinetic analyses of the individual events in the ATPase cycle revealed that each mutation alters different steps in this cycle. For example, different mutations gave enhanced or reduced rate constants of ATP binding, ATP hydrolysis, or ADP release or exhibited altered ATP, ADP, or actin affinity. Local effects dominated, no common pattern accounted for the similar mutant phenotype, and there was no distinct set of changes that distinguished DCM mutations from previously analyzed HCM myosin mutations. That said, using our data to model the complete ATPase contraction cycle revealed additional critical insights. Four of the DCM mutations lowered the duty ratio (the ATPase cycle portion when myosin strongly binds actin) because of reduced occupancy of the force-holding A·M.D complex in the steady-state. Under load, the A·M·D state is predicted to increase owing to a reduced rate constant for ADP release, and this effect was blunted for all five DCM mutations. We observed the opposite effects for two HCM mutations, namely R403Q and R453C. Moreover, the analysis predicted more economical use of ATP by the DCM mutants than by WT and the HCM mutants. Our findings indicate that DCM mutants have a deficit in force generation and force holding capacity due to the reduced occupancy of the force-holding state.

Item Type: Article
Uncontrolled keywords: Human cardiomyopathies, hypertrophic cardiomyopathies, dilated cardiomyopathies, actin & myosin ATPase, kinetic modelling
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Michael Geeves
Date Deposited: 19 Apr 2018 09:09 UTC
Last Modified: 20 Apr 2018 11:59 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/66792 (The current URI for this page, for reference purposes)
Geeves, Michael A.: https://orcid.org/0000-0002-9364-8898
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